Catalytic Activities of Cu(II) Complexes with Nitrogen-Chelating

7892

J. Org. Chem. 2001, 66, 7892-7897

Catalytic Activities of Cu(II) Complexes with Nitrogen-Chelating Bidentate Ligands in the Coupling of Imidazoles with Arylboronic Acids James P. Collman,* Min Zhong, Chi Zhang, and Simona Costanzo Department of Chemistry, Stanford University, Stanford, California 94305-5080 [email protected] Received June 15, 2001

Introduction N-Arylimidazoles are common motifs in pharmaceutical research because of their biomedical use as thromboxane synthase inhibitors,1 AMP phosphodiesterase inhibitors,2 AMPA receptor antagonists,3 cardiotonic4 and topical antiglaucoma agents,5 etc. Moreover, recent highresolution X-ray diffraction analyses have revealed in the CuB site of cytochrome c oxidase (CcO), the terminal respiratory enzyme of mitochondria and aerobic bacteria,6 a tyrosine-histidine (Tyr244-His240) cross-linked through a C-N bond.7 This functionalized phenol has been postulated to serve as a hydrogen atom donor during the 4H+, 4e- reduction of O2 to H2O.8 Thus, in the course of our efforts in developing new active-site models of CcO,9 * To whom correspondence should be addressed. Tel: (650) 7250283. Fax: (650) 725-0259. (1) (a) Iizuka, K.; Akahane, K.; Momose, D. I.; Nakazawa, M.; Tanouchi, T.; Kawamura, M.; Ohyama, I.; Kajiwara, I.; Ignchi, Y.; Okada, T.; Taniguchi, K.; Miyamoto, T.; Hayashi, M. J. Med. Chem. 1981, 24, 1139-1148. (b) Cozzi, P.; Carganico, G.; Fusar, D.; Grossoni, M.; Menichincheri, M.; Pinciroli, V.; Tonani, R.; Vaghi, F.; Salvati, P. J. Med. Chem. 1993, 36, 2964-2972. (2) (a) Venuti, M. C.; Stephenson, R. A.; Alvarez, R.; Bruno, J. J.; Strosberg, A. M. J. Med. Chem. 1988, 31, 2136-2145. (b) Martinez, G. R.; Walker, K. A. M.; Hirschfeld, D. R.; Bruno, J. J.; Yang, D. S.; Maloney, P. J. J. Med. Chem. 1992, 35, 620-628. (3) Ohmori, J.; Shimizu-Sasamata, M.; Okada, M.; Sakamoto, S. J. Med. Chem. 1996, 39, 3971-3979. (4) (a) Sircar, I.; Duell, B. L.; Bobowski, G.; Bristol, J. A.; Evans, D. B. J. Med. Chem. 1985, 28, 1405-1413. (b) Sircar, I.; Weishaar, R. E.; Kobylarz, D.; Moos, W. H.; Bristol, J. A. J. Med. Chem. 1987, 30, 19551962. (c) Gu¨ngo¨r, T.; Fouquet, A.; Teulon, J.-M.; Provost, D.; Cazes, M.; Cloarec, A. J. Med. Chem. 1992, 35, 4455-4463. (5) Lo, Y. S.; Nolan, J. C.; Maren, T. H.; Welstead, W. J., Jr.; Gripshover, D. F.; Shamblee, D. A. J. Med. Chem. 1992, 35, 47904794. (6) Ferguson-Miller, S.; Babcock, G. T. Chem. Rev. 1996, 96, 28892907 and references therein. (7) (a) Ostermeier, C.; Harrenga, A.; Ermler, U.; Michel, H. Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 10547-10553. (b) Yoshikawa, S.; Shinzawa-Itoh, K.; Nakashima, R.; Yaono, R.; Yamashita, E.; Inoue, N.; Yao, M.; Fei, M. J.; Libeu, C. P.; Mizushima, T.; Yamaguchi, H.; Tomizaki, T.; Tsukihara, T. Science 1998, 280, 1723-1729. (8) (a) Gennis, R. B. Biochim. Biophys. Acta 1998, 1365, 241-248. (b) Sucheta, A.; Szundi, I.; Einarsdottir, O. Biochemistry 1998, 37, 17905-17914. (c) MacMillan, F.; Kannt, A.; Behr, J.; Prisner T.; Michel, H. Biochemistry 1999, 38, 9179-9184. (d) Proshlyakov, D. A.; Pressler M. A.; DeMaso C.; Leykam, J. F.; DeWitt, D. L., Babcock G. T. Science 2000, 290, 1588-1591. (e) Proshlyakov, D. A.; Pressler M. A.; Babcock G. T. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 8020-8025. (9) (a) Collman, J. P.; Fu, L.; Herrmann, P. C.; Zhang, X. M. Science 1997, 275, 949-951. (b) Collman, J. P. Inorg. Chem. 1997, 36, 51455155. (c) Collman, J. P.; Eberspacher, T.; Fu, L.; Herrmann, P. C. J. Mol. Catal. A: Chem. 1997, 117, 9-20. (d) Collman, J. P.; Fu, L. Acc. Chem. Res. 1999, 32, 455-463. (e) Collman, J. P.; Rapta, M.; Broring, M.; Raptova, L.; Schwenninger, R.; Boitrel, B.; Fu, L.; L’Her, M. J. Am. Chem. Soc. 1999, 121, 1387-1388. (f). Collman, J. P.; Zhong, M.; Wang, Z.; Rapta, M.; Rose, E. Org. Lett. 1999, 1, 2121-2124.

we became interested in studying direct C-N coupling reactions for preparing N-arylimidazoles as building blocks10 of new model compounds incorporating N-(2′hydroxyphenyl)imidazole moieties as CuB site mimics. Numerous reports describe copper-promoted N-arylation of imidazoles with arylmetalloids to furnish Narylimidazoles. Traditional Ullman-type coupling of imidazole with aryl halides,1-5,11 one of the most usually used methods, requires high temperatures. A few approaches have also been developed using aryllead, arylborane, or arylsilane reagents in the presence of Cu(OAc)2 under milder conditions. For example, Lo´pez-Alvarado12 described the coupling of imidazoles with p-tolyllead triacetate in the presence of a stoichiometric amount of Cu(OAc)2 at 90 °C. Interestingly, Konopelski13 found that imidazoles react with o- or p-methoxyphenyllead triacetate to give the corresponding C-N coupling products in good yields in the presence of 10% mol of Cu(OAc)2 at room temperature. However, it should be noted that both procedures produce toxic organolead byproducts. Moreover, Chan and Lam14 established an efficient approach to N-arylimidazoles via Cu(OAc)2-mediated coupling of imidazoles with readily available arylboronic acids at room temperature,15 and Lam16 extended this methodology to phenyl trimethoxysilane. Although both methods are quite mild, they suffer from two main drawbacks: more than an equimolar amount of Cu(OAc)2 and either Et3N or pyridine are employed to promote the coupling; moreover, the synthesis of phenyl trimethoxysilane involves the use of highly toxic trimethoxysilane.17 Very recently, both Lam18 and Buchwald19 reported the synthesis of N-arylimidazoles through the coupling of imidazoles with p-tolylboronic acid using 10% mol of Cu(10) (a) Collman, J. P.; Wang, Z.; Zhong, M.; Zeng, L. J. Chem. Soc., Perkin Trans. 1 2000, 1217-1221. (b) Collman, J. P.; Zhong, M.; Wang, Z. Org. Lett. 1999, 1, 949-951. (11) Kiyomori, A.; Marcoux, J.-F.; Buchwald, S. L. Tetrahedron Lett. 1999, 40, 2657-2660. (12) (a) Lo´pez-Alvarado, P.; Avendan˜o, C.; Mene´ndez, J. C. Tetrahedron Lett. 1992, 33, 659-662. (b) Lo´pez-Alvarado, P.; Avendan˜o, C.; Mene´ndez, J. C. J. Org. Chem. 1995, 60, 5678-5682. (13) Elliott, G. I.; Konopelski, J. P. Org. Lett. 2000, 2, 3055-3057. (14) (a) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 29412944. (b) Combs, A. P.; Saubern, S.; Rafalski, M.; Lam, P. Y. S. Tetrahedron Lett. 1999, 40, 1623-1626. (c) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Averill, K. M.; Chan, D. M. T.; Combs, A. Synlett 2000, 674-676. (15) This system was also successfully applied to other types of coupling reactions. For N-arylation of NH-containing heterocycles, see: (a) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. Tetrahedron Lett. 1998, 39, 2933-2936. (b) Cundy, D. J.; Forsyth, S. A. Tetrahedron Lett. 1998, 39, 7979-7982. (c) Mederski, W. W. K. R.; Lefort, M.; Germann, M.; Kux, D. Tetrahedron 1999, 55, 12757-12770. (d) Lam, P. Y. S.; Deudon, S.; Hauptman, E.; Clark, C. G. Tetrahedron Lett. 2001, 42, 2427-2429. For O-arylation of phenols, see: (e) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39, 2937-2940. (f) Jung, M. E.; Lazarova, T. I. J. Org. Chem. 1999, 64, 2976-2977. (g) Decicco, C. P.; Song, Y.; Evans, D. A. Org. Lett. 2001, 3, 10291032. (h) Simon, J.; Salzbrunn, S.; Prakash, G. K. S.; Petasis, N. A.; Olah, G. A. J. Org. Chem. 2001, 66, 633-634. For O-arylation of N-hydroxyphthalimide, see: (i) Petrassi, H. M.; Sharpless, K. B.; Kelly, J. W. Org. Lett. 2001, 3, 139-142. For S-arylation of thiols, see: (j) Herradura, P. S.; Pendola, K. A.; Guy, R. K. Org. Lett. 2000, 2, 20192022. (16) Lam, P. Y. S.; Deudon, S.; Averill, K. M.; Li, R. H.; He, M. Y.; DeShong, P.; Clark, C. G. J. Am. Chem. Soc. 2000, 122, 7600-7601. (17) Murata, M.; Suzuki, K.; Watanabe, S.; Masuda, Y. J. Org. Chem. 1997, 62, 8569-8571 and references therein. (18) Lam, P. Y. S.; Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav, P. K. Tetrahedron Lett. 2001, 42, 3415-3418. (19) Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3, 2077-2079

10.1021/jo010615u CCC: $20.00 © 2001 American Chemical Society Published on Web 10/19/2001

Notes

J. Org. Chem., Vol. 66, No. 23, 2001 7893

Table 1. Effect of the Bidentate Ligand on the Reactivity of Complex 3 in the N-Arylation of Imidazole (1a) with Phenylboronic Acid (2a)

a A typical procedure: a mixture of 1 mmol of imidazole (1a), 2 mmol of phenylboronic acid (2a), and 0.1 mmol of Cu(II) complex (3) in 4 mL of dry CH2Cl2 was stirred at room temperature overnight under an atmosphere of dioxygen. b Isolated yield.

(OAc)2. However, Lam’s method requires more than a stoichiometric amount of oxidant, such as pyridine Noxide, TEMPO, or NMO etc., as well as Et3N or pyridine, and elevated temperature (65 °C), whereas the system described by Buchwald requires the addition of a stoichiometric amount of 2,6-lutidine as well as myristic acid and gives a low yield (32%). Accordingly, it is important to develop more efficient catalytic systems to prepare N-arylimidazoles under mild reaction conditionssat room

temperature, with a small amount of the catalyst, and in the absence of base. Recently, we carried out the coupling of imidazoles with arylboronic acids at room temperature using only 10% mol of [Cu(OH)‚TMEDA]2Cl2, without the addition of base in CH2Cl2.20a We also demonstrated that this coupling could be performed in water to give N-arylimidazoles in moderate yields.20b To the best of our knowledge, this catalytic system is one of the most efficient

7894

J. Org. Chem., Vol. 66, No. 23, 2001

Table 2. Effect of the Counterion on the Reactivity of Complex 3 in the N-Arylation of Imidazole (1a) with Phenylboronic Acid (2a)

a A typical procedure: a mixture of 1 mmol of imidazole (1a), 2 mmol of phenylboronic acid (2a), and 0.1 mmol of Cu(II) complex (3) in 4 mL of dry CH2Cl2 was stirred at room temperature overnight under an atmosphere of dioxygen. b Isolated yield.

approaches to N-arylimidazoles to date. To design and synthesize more efficient catalysts for this important C-N coupling, it is necessary to understand the effects of bidentate ligands as well as counterions on the activities of the µ-hydroxo Cu(II) complexes. Thus, a series of µ-hydroxo Cu(II) complexes with nitrogen chelating bidentate ligands were prepared and applied to the coupling of imidazoles with arylboronic acids. Results and Discussion [Cu(OH)‚TMEDA]2Cl2 is a binuclear bis-µ-hydroxo copper(II) complex.21 It has been demonstrated to be an efficient catalyst for oxidative coupling reactions of naphthols22 or terminal alkynes.23 In our studies, all Cu(II) complexes (3) were prepared24 by stirring 1 equiv of the bidentate ligand (L) with 1 equiv of CuX (X ) Cl-, Br-, I-, or TfO-) in 95% aqueous ethanol at room temperature overnight under an atmosphere of dioxygen. These Cu(II) complexes (3) were used in the C-N coupling reaction following our previously published procedure:20a a mixture of 1 mmol of imidazole (1a), 2 equiv of phenylboronic acid (2a), and 0.1 equiv of Cu(II) complex (3) in 4 mL of dry CH2Cl2 was stirred at room temperature overnight under an atmosphere of dioxygen. (20) (a) Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233-1236. (b) Collman, J. P.; Zhong, M.; Zeng, L.; Costanzo, S. J. Org. Chem. 2001, 66, 1528-1531. (21) Banci, L.; Bencini, A.; Gatteschi, D. J. Am. Chem. Soc. 1983, 105, 761-764 and references therein. (22) (a) Noji, M.; Nakajima, M.; Koga, K. Tetrahedron Lett. 1994, 35, 7983-7984. (b) Nakajima, M.; Miyoshi, I.; Kanayama, K.; Hashimoto, S.; Noji, M.; Koga, K. J. Org. Chem. 1999, 64, 2264-2271. (23) Hay, A. S. J. Org. Chem. 1962, 27, 3320-3321. (24) (a) McWhinnie, W. R. J. Chem. Soc. 1964, 2959. (b) Ferraro, J. R.; Walker, W. R. Inorg. Chem. 1965, 4, 1385. (c) Harris, C. M.; Sinn, E.; Walker, W. R.; Wolliams, P. R. Aust. J. Chem. 1968, 21, 631.

Notes

As shown in Table 1, several bisimidazole-type ligands L1-4 were initially investigated. The coupling yield of N-phenylimidazole (4a) is not significantly affected by either replacing the methylene with a carbonyl group or changing the N-methyl to N-octyl groups of ligand L1. However, the increase of the substituents’ bulk on the carbons adjacent to the imidazole sp2-N atoms, serving as chelating centers, results in a significantly decreased yield of compound 4a (entries 1-4, Table 1). Other types of sp2-N bidentate ligands have also been tested. The Cu(II) complexes with 2,2′-pyridyl (L5) or 1,10-phenatholine (L6) also catalyze the coupling to give compound 4a in moderate yields (entries 5 and 6, Table 1). However, no coupling product is formed when employing 2, 2′-dipyridylmethane or 2, 2′-dipyridyl ketone as the ligand. A series of sp3-N bidentate ligands were also investigated. A 61% yield of N-phenylimidazole (4a) is obtained when Proton Sponge (L7) is used (entry 7, Table 1). Both increasing the distance between the two dimethylamino groups and replacing one or both dimethylamino groups with bulkier dialkylamino groups on the TMEDA (L8) backbone result in decreased coupling yields (entries 8-13, Table 1). The Cu(II) complexes prepared from readily available ring-containing alkyldiamines, such as tetramethylcyclohexanediamine (L14), N,N-dimethylpiperazine (L15), Dabco (L16), and (-)-sparteine (L17) give moderate coupling yields (entries 14-17, Table 1). A relatively low yield of compound 4a is obtained when DBU (L18) is used as a ligand (entry 18, Table 1). The activity of Cu(II) complexes with different counterions were also tested (Table 2). Only small variations of the coupling yield are observed using TMEDA (L8) as a ligand with different counterions, such as Cl-, Br-, I-, and TfO-. However, in the case of Proton Sponge (L7), the coupling yield significantly drops when CuCl is replaced with CuBr. It should be noted that the complex derived from 1,10-phenatholene (L6) with CuBr or CuI does not give compound 4a. Some studies have shown that strongly coordinating counterions, such as halides, can affect the rate of reoxidation by acting as bridging ligands and thus favoring the formation of the active dinuclear bis-µ-hydroxo Cu(II) system.25 This could explain the variation in activity of the Cu(II) complexes in the presence of different counterions. Since regioselectivity is one of the major issues in various coupling reactions, Cu(II) complexes (3) with different ligands were applied to the coupling of equimolar amounts of 4(5)-substituted imidazole (1b or 1c) with o-tolylboronic acid (2b) (Table 3). The increase of either the number of carbons or the bulk of the substituents on the nitrogen atoms of TMEDA (L8) results in small variations of the selectivity. No obvious linear correlation is observed between steric hindrance in the bidentate ligands and the regio-selectivity of the coupling products. In general, better coupling yields and selectivities are obtained by employing 4(5)-phenylimidazole (1c) instead of 4(5)-methylimidazole (1b) as a substrate. In our proposed mechanism for the C-N coupling of imidazoles, phenylboronic acid (2) initially undergoes transmetalation with complex 3 to generate boric acid (5) and intermediate 6, which then coordinates the imidazole substrate (1) forming complex 7. In the pres(25) (a) Viersen, F. J.; Challa, G.; Reedijk, J. Recl. Trav. Chim. PaysBas, 1989, 108, 247-255. (b) Garozzo, M. S.; Marsich, N.; Camus, A. Gazz. Chim. Ital. 1993, 123, 697-701.

Notes

J. Org. Chem., Vol. 66, No. 23, 2001 7895

Table 3. Effect of the Ligand of Cu(II) Complex (3) on the Regioselectivity of the Coupling Reaction of 4(5)-Substituted Imidazole (1b or 1c) with O-Tolylboronic Acid (2b)

a A typical procedure: a mixture of 1 mmol of 4(5)-substituted imidazole (1b or 1c), 1 mmol of o-tolylboronic acid (2b), and 0.1 mmol of Cu(II) complex (3) in 4 mL of dry CH2Cl2 was stirred at room temperature overnight under an atmosphere of dioxygen. b Isolated yield. c The ratio of compounds 4b and 4b′, as well as 4c and 4c′, was determined by the comparison of the respective methyl group signals in the corresponding 1H NMR spectrum using CDCl3 as the solvent; see the Supporting Information of ref 20a.

ence of dioxygen, complex 7 is proposed to be oxidized forming a putative Cu(III) intermediate 8, which undergoes reductive elimination yielding N-phenylimidazole 4 and complex 9. The latter can be reconverted to bis-µhydroxo Cu(II) complex 3 in the presence of dioxygen and water.26 It is most likely that less sterically hindered bidentate ligands form intermediate 7 or 8 more easily compared with hindered ligands, resulting in higher yields of coupling product 4 (Scheme 1). (26) De Jong, C. R. H. I. In Organic Syntheses by Oxidation with Metal Compounds; Mijs, W. J., de Jong, C. R. H. I., Eds.; Plenum Press Inc.: New York, 1986; pp 423-443.

The regioselectivity of coupling is dependent on the interaction between RL and RS on the bidentate ligands, R3 on the phenyl and R4 on imidazole rings. As shown in Scheme 2, regardless of the bulk of the substituents RL and RS, the intermediates 7F and 7F′ are more geometrically favored than the intermediates 7U and 7U′, resulting in a higher yield of 4b or 4c compared with 4b′ or 4c′. Moreover, in the case of ethylenediamine-based ligands, TMEDA (L8) gives the highest selectivity compared with other more hindered ligands (L11-L13). It is possible that the increase in the bulk of RL enhances the interactions between RL, R3, R4, and the counterion,

7896

J. Org. Chem., Vol. 66, No. 23, 2001

Notes Scheme 1

Scheme 2

TMEDA (L8) appears to be the best ligand for the coupling reaction. Detailed mechanistic studies of the reaction and the application of these new catalysts to the coupling of other NH- containing substrates27 with arylboronic acids are being investigated and will be reported in due course. Experimental Section

reducing the number of stable conformations of intermediates 7U and 7F and therefore yielding lower ratios of 4b/4b′ or 4c/4c′ compared with TMEDA (L8). In summary, we have demonstrated that a series of nitrogen chelating bidentate ligands (L) can react with Cu(I) salt and water in the presence of dioxygen to generate Cu(II) complexes (3) that efficiently catalyze the coupling reaction of imidazoles with arylboronic acids under mild conditions. The activities of the Cu(II) complexes (3) are dependent both on the nature of the bidentate ligands (L) and the counterions employed and

All reagents were used as supplied commercially without further purification unless otherwise noted.Bis[2-(1-methylimidazolyl)]methane (L1),28 bis[2-(1-methylimidazolyl)]ketone (L2),28 bis[2-(1-octylimidazolyl)]ketone (L3),9f bis[2-(4,5-diphenyl-1-methylimidazolyl)]ketone (L4),9f N,N′-tert-butyl-N,N′-dimethylethylenediamine (L12),29 and N,N,N′,N′-tetramethyl-1,2-cyclohexanediamine (L14)30 were prepared following reported procedures. 1H and 13C NMR spectra were recorded on Varian XL-400 instruments. Mass spectra were measured by the Mass Spectrometry Facility at the University of California, San Francisco. N,N-Diisopropyl-N′,N′-dimethylethylenediamine (L13). This compound was prepared following the procedure for the synthesis of N,N,N′,N′-tetramethyl-1,2-cyclohexanediamine (L14)30 using N,N-diisopropylethylenediamine as starting material. Colorless liquid, 67% yield. 1H NMR (CDCl3): δ 2.99 (m, 2H), 2.52 (m, 2H), 2.30 (m, 2H), 2.24 (s, 6H), 1.00 (d, J ) 6.5 Hz, 12H) ppm. 13C NMR (CDCl3): δ 61.8, 49.3, 45.9, 43.9, 20.6 ppm. MS (m/z): 172 (M+), 162, 143, 114 (100), 82, 72, 58. HRMS: calcd for C10H24N2 (M+) 172.194, found 172.195. General Procedure for the Preparation of Bidentate Ligand‚Cu(II) Complexes (3). A mixture of 3 mmol of bidentate ligand (L) and 3 mmol of CuX (X = Cl-, Br-, I-, or TfO-) in 6 mL of 95% aqueous ethanol was stirred vigorously at room temperature overnight under an atmosphere of dioxygen. The precipitates were filtered off, washed with a small amount of 95% ethanol, and dried in vacuo over P2O5. In some cases, the complexes are soluble in 95% aqueous ethanol and they were obtained by concentrating to dryness and dried in vacuo over (27) Lam recently disclosed that [Cu(OH)‚TMEDA]2Cl2 can also catalyze the C-N coupling reactions of phenyl trimethoxysiloxane with benzoimidazole (ref 16) and p-tolylboronic acid with various NHcontaining heterocycles (ref 18) in moderate yields. (28) Elgafi, S.; Field, L. D.; Messerle, B. A.; Hambley, T. W.; Turner, P. J. Chem. Soc., Dalton Trans. 1997, 2341-2345. (29) Mahadevan, V.; Henson, M. J.; Solomon, E. I.; Stack, T. D. P. J. Am. Chem. Soc. 2000, 122, 10249-10250. (30) Remenar, J. F.; Lucht, B. L.; Collum, D. B. J. Am. Chem. Soc. 1997, 119, 5567-5572.

Notes P2O5. These complexes were used for the coupling reaction without further purification and all the molecular weights of these complexes were calculated on the basis of the formula of [Cu(OH)‚L]2X2. General Procedure for the N-Arylation of Imidazoles. A mixture of 1 mmol of imidazole (1), 2 mmol of arylboronic acid (2), and 0.1 mmol of µ-hydroxo Cu(II) complex 3 in 4 mL of dry CH2Cl2 was vigorously stirred at room temperature overnight under an atmosphere of dioxygen. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by preparative thin-layer chromatography on a 1000 µm silica gel plate using a mixed solvent of CHCl3 and n-hexane

J. Org. Chem., Vol. 66, No. 23, 2001 7897 (1/1 volume ratio, saturated with NH3 gas) to give N-arylimidazole (4).

Acknowledgment. We thank the National Institutes of Health (NIH) (Grant No. GM 17880) for the financial support of this work. We also thank the Mass Spectrometry Facility at the University of California at San Francisco supported by the NIH (Grant Nos. RR 04112 and RR 01614). JO010615U